Migraine headache affects approximately 20% of the population (predominantly women) and is one of the main causes for loss of work. Although the headache phase involves cerebral and extracerebral blood vessels and perivascular trigeminal nerve fibers, the triggering mechanisms of migraine are not known. Several events are known to anticipate and possibly trigger migraine headaches such as the aura. We recently demonstrated that cortical spreading depression (CSD) an intrinsic brain parencymal event underlying migraine visual aura initiates a cascade of events in the overlying meninges consistent with trigeminovascular activation and compatible with lateralized head pain. Nitroglycerin (a prodrug for Nitric Oxide) administered to migraineurs triggers the typical migraine headaches 4-6 hours after infusion (in migraineurs but not control subjects) and promotes delayed inflammation and new gene expression in dura mater consistent with development of headache. In this proposal we will address three specific aims; the first aim will investigate how intense brain activity within the brain parenchyma (CSD) activates meninges and perivascular trigeminal nerve axons through the gila limitans and blood brain barrier. Aim 2 will study the role of matrix metalloproteinases (MMP) in CSD triggered trigeminal activation. Aim 3 will examine whether MMP activation via NO generation (nitroglycerin) is common to both triggers. These goals are intended to extend novel findings and provide evidence for a common mechanism for trigeminal activation by events known to trigger headache. This proposed research will be done primarily in Ankara, Turkey at Gazi University by Associate Professor Dr. Hayrunnisa Bolay in collaboration with Prof. Dr. Michael A. Moskowitz from Massachusetts General Hospital, as an extension of NIH grant (PO1 NS35611, Migraine Pathophysiology and Treatment Mechanisms).